Formulation design for children: where to begin?
Start with consideration of the intended therapeutic effect.
Decide what shape do you need the plasma concentration vs time profile to be?
How old are paediatric patients?
Anywhere from zero to 18 years!
Neonate - 0-27 days Infant - 1-23 months Child - 2-11 years Adolescent - 12-18 years Adult - >18 years
The formulation type you select will depend on a combination of factors. These are:
- Desired PK profile (rate and extent of exposure)
- Acceptability for the intended age group(s)*
- -> Swallowability
- -> Taste, texture
- -> Ease of administration (carers)
Pharmaceutical factors:
- API properties – physchem and material attributes
- Dose range – these can be fairly wide especially at the start of development
- Suitability of excipients
Biopharmaceutics:
The study of the factors influencing the bioavailability of drug in man and the use of this information to optimise pharmacologic or therapeutic activity of drug products in clinical applications.
Factors influencing bioavailability:
- Solubility
- Dissolution
- Permeability
- First pass metabolism
PK and absorption differences in children?
- In biological terms, children are not just shrunken-down adults
- Physiological changes that occur as children grow and mature can alter absorption and pharmacokinetics.
Changes occur in:
- -> Saliva production
- -> Gastric pH and emptying rate
- -> Intestinal transit, surface area and motility
- -> Drug metabolising enzymes
- -> Drug efflux transporters
Differences in the GI tract (dissolution) ?
- Reduced acid secretion in neonates may increase bioavailability of acid labile drugs
- Increased gastric solublity of acidic drugs and decreased solubility of basic drugs in neonates.
- Impact on pH sensitive coatings.
- Saliva flow rate: impact on orally retained dosage forms e.g. orally disintegrating tablets, chewable tablets and thin films
- Stomach capacity: impact on volume of liquid the patient is likely to drink when taking solid dosage forms
Differences in the GI tract (transit)?
- Irregular intestinal motility in paediatric patients leads to very variable transit times
- Source of variability in product performance, especially for controlled release formulations
Differences in the GI tract (permeability)?
- GI tract increases in length and diameter continuously from birth till growth is complete.
- Permeability across the gut wall2 - generally permeability appears to decrease with age but unclear when adult values are reached
- P-Gp efflux transporter expression increases with age in rats and mice, however conflicting reports in man
Differences in the GI tract (metabolism)?
Gut wall–> CYP3A: expressed in all children over 6 months and half of those <6 months based on biopsy data
Hepatic –> CYPs generally present from birth and reach adult levels at 2-5 years depending on isoform
UGTs reach adult levels at different ages depending on isoform (anywhere between <2yrs and 18 years)
Children generally have a larger liver size and hepatic blood flow per body weight than adults
Formulation bridging?
Formulation bridging – assessing the rate and extent of absorption from one formulation vs another.
i.e. if I switch between these two products, will I get the same Cmax and AUC?
What is relative bioavailability?
Comparing Cmax and AUC between two products
Bioequivalence definiton:
Assessing statistical equivalence of Cmax and AUC from two different products using a confidence intervals approach (regulatory standard)
Why do we need formulation bridging for paediatrics?
- To select an appropriate dose , i.e. make sure the exposure you’re expecting is what you get – avoid unanticipated toxic effects
- For chronic illnesses, the patient may be receiving treatment from a young age into adulthood – need to know whether any dose adjustment is required when switching between the different formulation types
Paediatric formulation bridging - how?
Relative bioavailability study
- Healthy adult volunteers – unethical to perform in children
- Comparison between adult and pediatric formulations to support dosing selection in pediatric clinical trials.
- Comparing the final pediatric formulation to be used in pivotal studies to earlier formulations.
In vitro testing
- Dissolution studies to compare formulation performance
- Consider biorelevant media, volumes, agitation
If a solution and tablet are bioequivalent in adults, will they also be equivalent in children?
Not always
–> Smaller volumes for dissolution, different gastric pH etc. may lead to a different result depending on what the important factors are for drug absorption from the tablet
What is in silico PBPK modelling?
Physiologically based pharmacokinetic modelling.
A key tool to help put all of the pieces together and work out what the overall impact on formulation performance
Mechanistically simulates the processes involved in absorption and PK performance
Food can affect formulation performance and drug absorption in a number of ways:
- Altered composition of GI fluid,
- Different gastric emptying rates,
- Altered blood flow,
- Drug binding to food components,
Peadiatric patients will eat differently to adult patients.
Mixing paediatric medicines with food:
- Paediatric medicines are sometimes mixed with food to make them acceptable to the child
- The BNF-C lists 11 drugs that are recommended to be given with food for this purpose
- This could have unintended consequences and the impact needs to be carefully considered, such as:
pH-dependant release mechanisms e.g. enteric coats
Dissolution /release rate
Stability of the API
Why solid dosage form?
- High patient compliance
- Self administration
- Large scale manufacturing is feasible (economical)
- Accuracy of dose is maintained
- Tailor made release profile can be achieved
- Long shelf life and minimum microbial spillage
- Stringent Process conditions are not required (compared to sterile dosage forms).
- Easy to transport in bulk
- Product identification is easy
Definition of friability?
is the tendency for a tablet to chip, crumble or break following compression
Definition of crushing force?
the force required to break the tablet along a given axis
Definition of tensile strength ?
the stress required to induce flow in the material.
Definition of hardness:
the resistance of a material to a permanent shape change such as resistance to scratching or indentation.
